Process for preparing nitrooxyalkyl substituted esters of carboxylic acids, intermediates useful in said process and preparation thereof

ABSTRACT

The present invention refers to a process for preparing a compound of general formula (A), as reported in the description, wherein R is a radical of a drug and R1-R12 are hydrogen or alkyl groups, m, n, o, q, r and s are each independently an integer from 0 to 6, and p is 0 or 1, and X is O, S, SO, SO2, NR13 or PR13 or an aryl, heteroaryl group, said process comprising reacting a compound of formula (B) R—COOZ (B) wherein R is as defined above and Z is hydrogen or a cation selected from: Li+, Na+, K+, Ca++, Mg++, tetralkylammonium, tetralkylphosphonium, with a compound of formula (C), as reported in the description, wherein R1-R12 and m, n, o, p, q, r, s are as defined above and Y is a suitable leaving group.

The present invention relates to a process for preparing nitrooxyalkylsubstituted esters of carboxylic acids, to intermediates useful in saidprocess and to their preparation.

Many carboxylic acid nitrooxyalkyl esters are pharmacologically activeproducts. For example, 1,4-dihydropyridine derivatives having nitrooxymoieties at the C-3 and/or C-5 ester position have shown to be activecalcium-channel blockers similar to nifedipine and nicardipine (J. Chem.Soc. Perkin Trans I, 525 (1993)). In literature, several methods forsynthesizing nitrooxyalkyl esters are reported. In this way, thenitrooxy moiety may be for example introduced by nucleophilicsubstitution of a leaving group already present on the alkyl chain ofalkyl ester precursor. In particular, 2-(6-methoxy-2-naphtyl)-propionicacid 4-nitrooxybutyl ester has been synthesized reacting 4-chlorobutyl2-(6-methoxy-2-naphtyl)-propionate with silver nitrate (WO 95/09831),whereas 2-(benzoylphenyl)propionic acid 4-nitrooxybutyl ester(ketoprofen nitrooxybutyl ester) has been prepared reacting the2-(3-benzoylphenyl)propionic acid sodium salt with 1,4-dibromobutane togive the corresponding bromobutyl ester, which was then treated withsilver nitrate to yield the desired nitrooxy derivative. Both processeshave the disadvantage that during the introduction of nitrooxy group,impurities of difficult removal are often obtained, such as silver salts(AgCl, AgBr) and silver metal, this being prejudicial to the use of theend-products in therapeutic field, in which an improved purity is alwaysrequested.

A further known process for preparing the above mentioned nitrooxyalkylesters is the insertion of nitrooxyalkyl group by reacting thecarboxylic acid or a derivative thereof (halide) with a nitrooxyalkylalcohol or with a nitrooxyalkyl bromide. For example,2-(S)-(6-methoxy-2-naphtyl)-propionic acid 4-nitrooxybutyl ester isprepared treating the corresponding acid chloride with4-nitrooxybutan-1-ol in methylene chloride and in presence of potassiumcarbonate (WO 01/10814). This method has also the disadvantage thatseveral by-products are formed, being in fact very difficult to obtainnitrooxyalkyl alcohols and the acyl halide in a pure form; moreover, forexample 4-nitrooxybutan-1-ol is stable only in solution and it cannot beisolated as a pure substance.

It was thus an object of the present invention to provide a new processfor preparing carboxylic acid nitrooxyalkyl esters not having the abovementioned disadvantages and wherein impurities and by-products arepresent in an essentially negligible amount.

The present invention relates to a process for preparing a compound ofgeneral formula (A)

wherein R₁-R₁₂ are the same or different and independently are hydrogen,straight or branched C₁-C₆ alkyl, optionally substituted with aryl;m, n, o, q, r and s are each independently an integer from 0 to 6, and pis 0 or 1, andX is O, S, SO, SO₂, NR₁₃ or PRn, in which R₁₃ is hydrogen, C₁-C₆ alkyl,or X is selected from the group consisting of:

saturated or unsaturated C₅-C₇ cycloalkylene, optionally substitutedwith one or more straight or branched C₁-C₃ alkyl groups;

arylene, optionally substituted with one or more halogen atoms, straightor branched alkyl groups containing from 1 to 4 carbon atoms, or astraight or branched C₁-C₃ perfluoroalkyl;

a 5 or 6 member saturated, unsaturated, or aromatic heterocyclic ringselected from

wherein the bonds, when they have an undefined position, are intended tobe in any possible position in the ring;R is selected from:

wherein M is a carbon or nitrogen atom;R^(C) is selected from: H, OH, NH₂, R^(E)CONH—, R^(E)COO—, anheterocyclic residue with 5 or 6 atoms that may be aromatic, saturatedor unsaturated, containing one or more heteroatoms selected from oxygen,nitrogen or sulfur, and phenylamino (PhNH—), in which the aromatic ringmay be substituted with one or more substituents selected from the groupconsisting of halogen, preferably chlorine or fluorine, straight orbranched C₁-C₄-alkyl, for example methyl, straight or if possiblebranched perfluoroalkyl, for example trifluoromethyl;

R^(E) is selected from the group consisting of straight or branchedC₁-C₅-alkyl, phenyl substituted with OCOR^(F), wherein R^(F) is selectedfrom the group consisting of methyl, ethyl or straight or branchedC₂-C₆-alkyl or phenyl;

R^(D) is selected from: H, OH, halogen, —NH₂, straight or branchedC₁-C₆-alkoxy, perfluoroalkyl having from 1 to 4 carbon atoms, forexample —CF₂, mono o di-(C₁-C₆)alkylamino; with the proviso that R^(C)and R^(D) can not be both H;

wherein R^(F1) and R^(F2) are halogens selected from chlorine, fluorineor bromine, R^(G) is hydrogen, straight or branched C₁-C₆-alkyl,preferably methyl;

wherein the bond at 6 position in formula (XXVIII) may be α or β;

wherein R′ in formula (XXXII) is H or RICO)—, in which R is selectedfrom the radicals represented by formulae (I)-(XXXI);in all the formulae (I-XXXII) listed above, the wavy line representsalways the position wherein —COO— group is bound;said process comprising reacting a compound of formula (B)

R—COOZ  (B)

wherein R is as above defined and Z is hydrogen or a cation selectedfrom Li+, Na+, K+, Ca++, Mg++, trialkylammonium tetralkylammonium,tetralkylphosphonium,with a compound of the following formula (C)

wherein R₁-R₁₂ and m, n, o, p, q, r, s are as defined above andY is selected from

an halogen atom such as Br, Cl, I;

—BF₄, —SbF₆, FSO₃—, R_(A)SO₃—, in which R_(A) is a straight or branchedC₁-C₆ alkyl, optionally substituted with one or more halogen atoms, or aC₁-C₆ alkylaryl;

R_(B)COO⁻, wherein R_(B) is straight or branched C₁-C₆ alkyl, aryl,optionally substituted with one or more halogen atoms or NO₂ groups,C₄-C₁₀ heteroaryl and containing one or more heteroatoms, which are thesame or different, selected from nitrogen, oxygen sulfur or phosphorus;

aryloxy optionally substituted with one or more halogen atoms or NO₂groups, or heteroaryloxy.

In particular when in formula (A) the R residue is as defined by formula(I), wherein M is a carbon atom, R^(C)=R^(E)COO— in 2 position, in whichR^(E) is CH₃ and R^(D)=H, the compound is known as acetylsalicylic acid;

when in formula (A) the R residue is represented by formula (I), whereinM is a carbon atom, R^(C)=NH₂ in 5 position, R^(D)=OH in 2 position, thecompound is known as mesalamine;when in formula (A) the R residue is represented by formula (I), inwhich M is a carbon atom, R^(D)=PhNH— in 2 position, wherein Ph- is the3-trifluoromethylbenzene radical, R^(D)=H, the compound is known asflufenamic acid;when in formula (A) the R residue is represented by formula (I), inwhich M is a carbon atom, R^(C)=PhNH— in 2 position, wherein Ph is the2,6-dichloro-3-methyl-benzene moiety, and R^(D)=H, the compound is knownas meclofenamic acid;when in formula (A) the R residue is represented by formula (I), inwhich M is a carbon atom, R^(C)=PhNH— in 2 position, wherein Ph e the2,3-dimethylbenzene radical, and R^(D)=H, the compound is known asmefenamic acid;when in formula (A) the R residue is defined by formula (I), in which Mis a carbon atom, R^(C)=PhNH— in 2 position, wherein Ph is a2-methyl-3-chlorobenzene group, and R^(D)=H, the compound is known astolfenamic acid;when in formula (A) the R residue is represented by formula (I), inwhich M is a nitrogen atom, R^(C)=PhNH— in 2 position, wherein Ph is the2-trifluoromethylbenzene radical, and R^(D)=H, the compound is known asniflumic acid;when in formula (A) the R residue is represented by formula (I), inwhich M is a nitrogen atom, R^(C)=PhNH— in 2 position, wherein Ph is the2-methyl-3-trifluoromethylbenzene radical, and R^(D)=H, the compound isknown as flunixin;when in formula (A) the R residue is represented by formula (II), inwhich e=0 and R^(E) is a methyl group, the compound is known asacetylsalicylsalicylic acid;when in formula (A) the R residue is defined by formula (III), thecompound is known as Ketorolac;when in formula (A) the R residue is represented by formula (IV), thecompound is known as etodolac;when in formula (A) the R residue is represented by formula (V), thecompound is known as pirazolac;when in formula (A) the R residue is defined by formula (VI), thecompound is known as tolmetin;when in formula (A) the R residue is defined by formula (VII), thecompound is known as bromfenac;when in formula (A) the R residue is represented by formula (VIII), thecompound is known as fenbufen;when in formula (A) the R residue is represented by formula (IX), thecompound is known as é mofezolac;when in formula (A) the R residue is represented by formula (X), whereinR^(F1) and R^(F2) are Cl and R^(G) is hydrogen, the compound is known asdiclofenac;when in formula (A) the R residue is defined by formula (X), whereinR^(F2) is chlorine, R^(F1) is fluorine and R^(G) is a methyl group, thecompound is known as COX-189;when in formula (A) the R residue is represented by formula (XI), thecompound is known as pemedolac;when in formula (A) the R residue is defined by formula (XII), thecompound is known as sulindac;when in formula (A) the R residue is defined by formula (XIII), thecompound is known as indomethacin;when in formula (A) the R residue is represented by formula (XIV), thecompound is known as suprofen;when in formula (A) the R residue is represented by formula (XV), thecompound is known as ketoprofen;when in formula (A) the R residue is represented by formula (XVI), thecompound is known as tiaprofenic acid;when in formula (A) the R residue is defined by formula (XVII), thecompound is known as fenoprofen;when in formula (A) the R residue is defined by formula (XVIII), thecompound is known as indoprofen;when in formula (A) the R residue is represented by formula (XIX), thecompound is known as carprofen;when in formula (A) the R residue is defined by formula (XXI), thecompound is known as loxoprofen;when in formula (A) the R residue is represented by formula (XXII), thecompound is known as ibuprofen;when in formula (A) the R residue is defined by formula (XXIII), thecompound is known as pranoprefen;when in formula (A) the R residue is defined by formula (XXIV), thecompound is known as bermoprofen;when in formula (A) the R residue is represented by formula (XXV), thecompound is known as CS-670;when in formula (A) the R residue is defined by formula (XXVI), thecompound is known as zaltoprofen;when in formula (A) the R residue is represented by formula (XXVII), thecompound is known as flurbiprofen;when in formula (A) the R residue is represented by formula (XXVIII), inwhich bond to the hydroxy group at 6 position is β standing, thecompound is known as ursodeoxycholic acid;when in formula (A) the R residue is represented by formula

(XXVIII), wherein bond to the hydroxy group at 6 position is α standing,the compound is known as chenodeoxycholic acid;

when in formula (A) the R residue is represented by formulae (XXIX) and(XXX), the compounds belong to the nifedipine class;when in formula (A) the R residue is defined by formula (XXXI), thecompound is known as apovincaminic acid;when in formula (A) the R residue is represented by formula (XXXII),wherein R′ is hydrogen, the compound is known as ferulic acid;

It has been surprisingly found that when in the compound of formula (B)R is the radical of formula (XXXII) wherein R′ is H (ferulic acid) thereaction is highly selective towards the formation of the ester offormula (A), in spite of the fact that the presence of two nucleophilicgroups in the ferulic acid (the carboxylic group and the fenolic group)could give a substantial formation of the nitroxyalkylether.

Preferably the present invention relates to a process for preparing acompound of formula (A) as above defined wherein:

the substituents R₁-R₁₂ are the same or different and independently arehydrogen or straight or branched C₁-C₃ alkyl,m, n, o, p, q, r and s are as defined above,

X is O, S or

Most preferably the present invention relates to a process for preparinga compound of formula (A) as above defined wherein R₁-R₄ and R₇-R₁₀ arehydrogens, m, n, q, r, are 1, and s are 0, p is 0 or 1, and X is O or S.

Preferred compounds of formula (C) as above defined are those wherein Yis selected from the group consisting of —BF₄, —SbF₆, FSO₃—, CF₃SO₃—,C₂F₆SO₃—, C₃F₇SO₃—, C₄F₉SO₃—, p-CH₃C₆H₄SO₃—.

The reaction is carried out in an organic solvent, generally an aprotic,dipolar solvent such as acetone, tetrahyrofurane, dimethylformamide,N-methylpyrrolidone, sulfolane, acetonitrile.

Alternatively the above reported reaction is carried out in a biphasicsystem comprising an organic solvent selected from toluene,chlorobenzene, nitrobenzene, tert-butyl-methylether and a water solutionwherein the organic solution contains (C) and the water solution containan alkaline metal salt of (B), in presence of a phase transfer catalystsuch as onium salts, for example tetralkylammonium andtetraalkylphosphonium salts.

The compounds of formula (B) and (C) are reacted at a (B)/(C) molarratio of 2-0.5, preferably of 1.5-0.7 and at a temperature ranging from0° C. to 100° C., preferably from 15° C. to 80° C.

The carboxylic acid salt may be prepared separately or may be generated“in situ”, for example performing the reaction between (B) and (C) inthe presence of a stoichiometric amount of a tertiary amine, oremploying an amount in excess of said amine.

Another object of the present invention is the preparation of compoundsof formula (C), by nitrating compounds of formula (D) reported herebelow, with a nitrating agent such as sulfonitric mixture and the like:

wherein M is OH, andY, X, m, n, o, p, q, r, s and R₁-R₁₂, have the meanings mentioned above.

Further object of the present invention is the preparation of compoundsof formula (C), characterized in that a compound of the followingformula (E) is reacted with nitrating agents selected for example fromalkaline metal nitrates, quaternary ammonium nitrates, quaternaryphosphonium salts and AgNO₃, Zn(NO₃)₂6H₂O:

wherein:Y, X, m, n, o, p, q, s and R₁-R₁₂, have the meanings mentioned above,

Another object of the present invention is the preparation of compoundsof formula (C), characterized in that a compound of formula (F)

wherein W is OH or halogen is reacted with a compound selected fromalkanoylsulfonylchloride, trifluoromethansulfonic acid anhydride when Wis OH or AgSbF₆, AgBF₄, AgClO₄, CF₃SO₃Ag, AgSO₃CH₃, CH₃C₆H₄SO₃Ag when Wis halogen.

Nitration of compound (D) was performed in an organic solvent, generallyin a solvent selected from acetone, tetrahydrofurane, dimethylformamide,N-methylpyrrolidone, sulfolane, acetonitrile, methylene chloride etc.,with nitrating agents selected from transition metal salts or, when M isOH, with nitrating systems based on nitric acid, such as the sulfonitricmixture.

The (D)/nitrating agent molar ratio is of from 2 to 0.5, in particularof 1.5 to 0.5.

Nitration was performed at a temperature ranging from 0° C. to 100° C.,preferably from 15° C. to 80° C.

The reaction product (C) may be isolated or its solution can be employedas such for the reaction with substrate (B) to give W.

Nitration of compound (E) was carried out in an organic solvent,generally in a solvent selected from acetone, tetrahydrofurane,dimethylformamide, N-methylpyrrolidone, sulfolane, acetonitrile,methylene chloride etc., with nucleophilic nitrating agents such asalkaline metal nitrates, onium salt nitrates, for exampletetraalkylammonium, tetraalkyl-phosphonium or trialkylammonium nitrateand so on.

Nitration was performed at a temperature of from 0° C. to 100° C., inparticular of 15° C. to 80° C.

The molar ratio between (E) and the nitrating agent is of from 20 to 2,preferably of 8 to 1.

The reaction product (C) may be isolated or its solution can be employedsuch as in the reaction with substrate (B) to give (A).

The reaction for obtaining compound (C) from (F) was carried out in anorganic solvent, generally selected from the group consisting ofacetone, tetrahydrofurane, dimethylformamide, N-methylpyrrolidone,sulfolane, acetonitrile, methylene chloride and the like, with areactive compound selected from transition metal salts of Y or, when Wis OH, the reaction was performed with an acid chloride such asmethanesulfonyl chloride etc., or with a suitable anhydride such astrifluoro-methanesulfonic anhydride.

The reaction was performed at a temperature ranging from −20° C. to 100°C., in particular from −20° to 60° C.

The molar ratio between (F) and the reagent is of from 2 to 0.5,preferably of 1.5 to 0.5.

The reaction product (C) may be isolated or its solution can be employedas such in the reaction with substrate (B) to give (A).

The following examples are to further illustrate the invention withoutlimiting it.

EXAMPLES Preparation of 4-nitrooxybutyl bromide according to Chem.Pharm. Bull., 1993, 41, 1040

Nitric acid (90%, 0.8 mol) was dropped under stirring in sulfuric acidmaintained at 0° C. (0.8 mol) and the mixture was then stirred at 0° C.for 80 minutes. In the solution thus obtained and maintained at 0° C.,under stirring 4-bromobutanol was dropped (0.4 mol) and the mixture wasstirred at the same temperature for additional 210 minutes. The solutionwas then poured in a water-ice mixture and extracted twice with diethylether. The ether extracts were combined together and washed with asodium bicarbonate saturated solution. The solvent was evaporated offunder vacuum to give a yellow oil (yield: 84.8%).

Example 1 Preparation of 4-nitrooxybutyl p-toluenesulfonate

To a solution of 4-bromobutanol (5.0 g, 33 mmol) in pyridine (50 ml)kept at 0° C., under stirring and under nitrogen atmosphere tosylchloride (6.8 g, 36 mmol) was added. The resulting solution was keptunder stirring for further 20 minutes and then stored overnight at −18°C. The reaction mixture was poured in a water/ice mixture (about 400 ml)and extracted with ethyl ether (500 ml). The organic phase was washedwith 6N hydrochloric acid (500 ml) and dried on sodium sulfate. Afterevaporation of the solvent under vacuum, an oily residue was obtained (7g). To a solution of the oily residue (7 g) in acetonitrile (50 ml) andmaintained under stirring at room temperature, silver nitrate (7.8 g, 46mmol) was added. After nearly 15 minutes, the formation of a yellow,insoluble product was observed. The heterogeneous mixture was kept understirring overnight. The insoluble was removed by filtration and thesolution was poured in water (200 ml) and extracted with ethyl ether(2×250 ml). The combined organic extracts were dried over sodiumsulfate. Evaporation of the solvent under vacuum afforded an oilyresidue (5 g).

Chromatography of the residue on silica gel (100 g), by hexane/ethylether mixture as eluent, gave the title product (3 g), m.p. 38-40° C.,purity higher than 98%, determined by HPLC.

FTIR (solid KBr, cm −1): 2966, 1626, 1355, 1281, 1177, 1097, 959, 876,815, 663, 553.

300 MHz 1H NMR (CDCl₃) delta 1.77 (m, 4H); 2.35 (s, 3H); 4.06 (m, 2H);4.38 (m, 2H); 7.36 (2H); 7.7 (2H).

Example 2A

Synthesis of (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid4-nitrooxybutyl ester

A mixture obtained pouring ferulic acid (1.94 g, 10 mmol),4-nitrooxybutyl bromide (1.98 g, 10 mmol) and triethylamine (1.21 g, 12mmol) in dimethylformamide (10 ml), was stirred for 3 days at 25° C.After evaporation in vacuo of DMF, an oil was obtained (2.3 g) that,according to NMR and HPLC analysis, mainly consists of unreacted ferulicacid and its 4-nitrooxybutyl ester. The ester was separated from acid byflash chromatography with a 65% yield.

Example 2B Synthesis of (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoicacid 4-nitrooxybutyl ester

(E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoic acid (670 mg, 3.46 mmol)and 4-(nitrooxy)butyl 4-p-toluensulfonate (1.00 g, 3.46 mmol) weredissolved in 40 ml of DMF and the solution poured in a three-neckedflask kept under argon and under magnetic stirrer. Subsequently,triethylamine (0.52 ml, 3.81 mmol) was added and the mixture was allowedto react at room temperature. The course of the reaction was followed byTLC (EtOAc as the eluent) and by LC/MS ESI using a RP-C18 4.6×100 mmcolumn. After 72 hours the reaction conversion was ca. 40%. Additional0.1 equivalents of tosylate were then added to the solution (100 mg,0.346 mmol) and the mixture was reacted for other 24 hours. After thisperiod the solution was poured in water and extracted with Et₂O (3×75ml). The combined organic phases were washed with a saturated solutionof NaHCO₃ and water, dried over Na₂SO₄ and concentrated under reducedpressure.

The residue was chromatographed over silica gel (using ethylacetate/petroleum ether 9:1 as the eluent) to provide the desired esterproduct in 70% yield.

The IR and LC-MS ESI- spectra of the peak product were identical tothose of an authentic sample.

Analyses

TLC: (Ethyl acetate) Rf=0.60

HPLC purity: 72%

MS (ESI neg): 310 (M-H)

IR (film) cm⁻¹: 3450 (br OH), 2964, 1707 (C═O), 1631(ONO₂), 1599, 1514,1448, 1280 (ONO₂)

Example 3A Synthesis of 5-t-butoxycarbonylamino-2-hydroxybenzoic acid4-(nitrooxy)butyl ester

The process of Example 2A was repeated, replacing however ferulic acidby 5-t-butoxycarbonylaminosalicilic acid. The title compound wasobtained with a yield of 50%.

Example 3B Synthesis of 5-t-butoxycarbonylamino-2-hydroxybenzoic acid4-(nitrooxy)butyl ester

To a mixture comprising DMF (200 ml), 5-t-butoxycarbonylaminosalicylicacid (4.37 g, 17.3 mmol) and 4-nitrooxybutyl p-toluenesulfonate (5 g,17.3 mmol), at room temperature and under stirring triethylamine wasadded (2.6 ml; 19 mmol). The reaction mixture was maintained 3 daysunder stirring at room temperature. It was then poured in water andextracted with ethyl ether. The combined organic phases were washed witha sodium carbonate solution and then with water. After drying on sodiumsulfate, the evaporation of the solvent yields a raw product thatpurified by silica gel chromatography gives the title compounds with ayield of 65%.

Example 4 Synthesis of potassium(E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate

Potassium hydroxide (580 mg, 10.3 mmol) was dissolved in methanol (10ml) and put in a three-necked flask. Stirring was set on. Subsequently,(E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoic acid (2.00 g, 10.3 mmol)in methanol (20 mL) was added to this solution through a funnel. Afterthe addition was ended, the solution was allowed to react at roomtemperature for 3 h. Methanol was then evaporated off and then yellowsolid residue was washed with Et₂O and dried under reduced pressure.

The product was obtained as a yellowish solid (2.40 g, quantitativeyield).

Analyses

IR (KBr) cm⁻¹: 3388, 1643, 1561 (C═O), 1524, 1404, 1263, 1204, 1152,1121.

Example 5A Synthesis of (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoicacid 4-(nitrooxy)butyl ester

Potassium (E)-3-(4-Hydroxy-3-methoxyphenyl)-2-propenoate (1.00 g, 4.3mmol) was dissolved in 40 ml of DMF and poured in a three-necked flaskkept under argon and magnetic stirring. The mixture was cooled at 0-5°C. through an ice bath and 4-(nitrooxy)butyl 4-p-toluensulfonate (1.25g, 4.3 mmol) in DMF (10 ml) was added through a funnel. After theaddition, the resulting mixture was stirred under argon, while thetemperature was allowed to rise to r.t. (25° C.). The reaction coursewas followed by TLC and LC/MS ESI−. After 6 hours the conversion wascomplete. The solution was then poured in water and extracted with Et₂O(3×75 ml). The combined organic phases were washed with a saturatedsolution of NaHCO₃ and water, dried over Na₂SO₄ and the volatilesremoved under reduced pressure to provide a residue. The residue waswashed with petroleum ether and dried under reduced pressure to providethe desire ester in 95% yield.

Analyses

HPLC purity: 95% MS (ESI neg): 310 (M-H)

IR (film) cm⁻¹: 3450 (br OH), 2964, 1707 (C═O), 1631(ONO₂), 1599, 1514,1448, 1280 (ONO₂).

¹H NMR (CDCl₃, 300 MHz): δ 1.72-1.93 (4H, m, CH₂—CH₂), 3.92 (3H, s,OCH₃), 4.22-4.26 (2H, m, CH₂—COO), 4.50-4.54 (2H, m, CH₂—OCN₂), 5.95(1H, br s, OH), 6.28 (1H, d, J=15.9 Hz, CH═), 7.03-7.10 (2H, m, aromaticH), 7.36 (1H, d, J=7.8 Hz, aromatic H), 7.61 (1H, d, J=15.9 Hz, CH═).

Example 5B Synthesis of (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoicacid 4-(nitrooxy)butyl ester

Ferulic acid (97 g, 0.50 mol) was dissolved in methanol (750 ml) andmixed with a solution of potassium hydroxide (33 g, 0.050 mol) inmethanol (250 ml) to give a clear solution at 27° C. The potassium saltof ferulic acid was precipitated by addition of toluene (1250 ml).

The suspension was cooled to 20° C., filtered, and washed with toluene(250 ml) and pentane (2×250 ml). The wet cake was dissolved in DMF (750ml), and potassium iodide (25 g) and crude 4-Bromo-1-butylnitrate (165g, 0.83 mol) were added. The reaction mixture was stirred for 16 hoursat 20-22° C. The reaction was added with water (750 ml) and theresulting mixture was extracted with t-Butyl-methylether (800 ml+500ml). The combined extracts were washed with water (750 ml), with 25%sodium chloride aqueous solution (250 ml), dried over sodium sulphate(250 g), filtered, and evaporated at 50° C. (external bath watertemperature) under vacuum to give a light brown oil (220 g). Cyclohexane(500 ml) was added, and the mixture was heated to 50° C. to give a twophases system, a colorless upper phase and a dark lower phase. Thestirred mixture was cooled to room temperature for 15 hours to give adark solid cake and a white suspension of fluffy material. The solid wascrushed and the suspension was filtered. The cake was washed withcyclohexane (2×50 ml) and dried at 45° C. to provide the desired ester(128.8 g) with 92% purity.

Analytically pure product was obtained by crystallization from toluene.

1. A process for preparing a compound of general formula (C)

wherein R₁-R₁₂ are the same or different and independently are hydrogen,straight or branched C₁-C₆ alkyl, optionally substituted with aryl; m,n, o, q, r and s are each independently an integer from 0 to 6, and p is0 or 1, and X is O, S, SO, SO₂, NR₁₃ or PR₁₃, in which R₁₃ is hydrogen,C₁-C₆ alkyl, or X is selected from the group consisting of: saturated orunsaturated C₅-C₇ cycloalkylene, optionally substituted with one or morestraight or branched C₁-C₃ alkyl groups; arylene, optionally substitutedwith one or more halogen atoms, straight or branched alkyl groupscontaining from 1 to 4 carbon atoms, or a straight or branched C₁-C₃perfluoroalkyl; a 5 or 6 member saturated, unsaturated, or aromaticheterocyclic ring selected from

Y is selected from a Br, Cl, I; —BF₄, —SbF₆, FSO₃—, R_(A)SO₃—, in whichRA is a straight or branched C₁-C₆ alkyl, optionally substituted withone or more halogen atoms, or a C₁-C₆ alkylaryl; R_(B)COO—, whereinR_(B) is straight or branched C₁-C₆ alkyl, aryl, optionally substitutedwith one or more halogen atoms or NO₂ groups, C₄-C₁₀ heteroaryl andcontaining one or more heteroatoms, which are the same or different,selected from nitrogen, oxygen sulfur or phosphorus; aryloxy optionallysubstituted with one or more halogen atoms or NO₂ groups, orheteroaryloxy; comprising reacting a compound of the following formula(E),

wherein R₁-R₁₂, m, n, o, p, q, r, s, X, Y are as defined above with anitrating agent.
 2. A process for preparing a compound of formula (C)according to claim 1 wherein the nitrating agent is selected fromalkaline metal nitrates, quaternary ammonium nitrates, quaternaryphosphonium nitrates, AgNO₃, Zn(NO₃)₂6H₂O.
 3. A process for preparing acompound of formula (C) according to claim 1 wherein the compound (E)and the nitrating agent are at molar ratio of 20:2.
 4. A process forpreparing a compound of formula (C) according to claim 1 wherein thereaction is performed at a temperature ranging from 0° C. to 100° C. 5.A process for preparing a compound of formula (C)

wherein R₁-R₁₂, m, n, o, p, q, r, s, X, are as defined in claim 1, andis selected from —BF₄, —SbF₆, FSO₃—, R_(A)SO₃—, in which R_(A) is astraight or branched C₁-C₆ alkyl, optionally substituted with one ormore halogen atoms, or a C₁-C₆ alkylaryl; R_(B)COO—, wherein R_(B) isstraight or branched C₁-C₆ alkyl, aryl, optionally substituted with oneor more halogen atoms or NO₂ groups, C₄-C₁₀ heteroaryl and containingone or more heteroatoms, which are the same or different, selected fromnitrogen, oxygen sulfur or phosphorus; aryloxy optionally substitutedwith one or more halogen atoms or NO₂ groups, or heteroaryloxy;comprising reacting a compound of the following formula (F),

wherein R₁-R₁₂, m, n, o, p, q, r, s, X, are as defined above, W is OH orhalogen, with a compound selected from alkanoylsulfonylchloride andtrifluoromethansulfonic anhydride when W is OH or with AgSbF₆, AgBF₄,CF₃SO₃Ag, AgSO₃CH₃, CH₃C₆H₄SO₃Ag when W is halogen.
 6. A process forpreparing a compound of formula (C) according to claim 5 wherein thecompound (F) and the nitrating agent are at molar ratio of 2:0.5.
 7. Aprocess for preparing a compound of formula (C) according to claim 5wherein the reaction is performed at a temperature ranging from 0° C. to100° C.